Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur
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ORIGINAL PAPER
Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur L. Felipe Barros1 · Iván Ruminot1 · Alejandro San Martín1 · Rodrigo Lerchundi1 · Ignacio Fernández‑Moncada1 · Felipe Baeza‑Lehnert1 Received: 10 September 2019 / Revised: 10 January 2020 / Accepted: 16 January 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Information processing is onerous. Curiously, active brain tissue does not fully oxidize glucose and instead generates a local surplus of lactate, a phenomenon termed aerobic glycolysis. Why engage in inefficient ATP production by glycolysis when energy demand is highest and oxygen is plentiful? Aerobic glycolysis is associated to classic biochemical effects known by the names of Pasteur, Warburg and Crabtree. Here we discuss these three interdependent phenomena in brain cells, in light of high-resolution data of neuronal and astrocytic metabolism in culture, tissue slices and in vivo, acquired with geneticallyencoded fluorescent sensors. These sensors are synthetic proteins that can be targeted to specific cell types and subcellular compartments, which change their fluorescence in response to variations in metabolite concentration. A major site of acute aerobic glycolysis is the astrocyte. In this cell, a Crabtree effect triggered by K+ coincides with a Warburg effect mediated by NO, superimposed on a slower longer-lasting Warburg effect caused by glutamate and possibly by N H4+. The compounded outcome is that more fuel (lactate) and more oxygen are made available to neurons, on demand. Meanwhile neurons consume both glucose and lactate, maintaining a strict balance between glycolysis and respiration, commanded by the N a+ pump. We conclude that activity-dependent Warburg and Crabtree effects in brain tissue, and the resulting aerobic glycolysis, do not reflect inefficient energy generation but the marshalling of astrocytes for the purpose of neuronal ATP generation. It remains to be seen whether neurons contribute to aerobic glycolysis under physiological conditions. Keywords Glucose · Lactate · Oxygen · Astrocytes · Neuron · Potassium · Nitric oxide · Glutamate · Ammonium
Introduction The full oxidation of glucose to CO2 and H2O renders 30–32 ATPs [1]. The alternative to oxidation is the production of lactate, which consumes no oxygen and produces only 2 ATPs. It was therefore surprising to see reports by Marcus Raichle and colleagues showing that evoked neural activity in human subjects is accompanied by glucose consumption in excess of oxygen consumption [2]. This finding was later confirmed by lactate measurements in humans and rodents [3, 4]. As the excess glycolysis occurred in the presence of oxygen, the phenomenon was a puzzling physiological counterpart to the aerobic glycolysis originally described in
Special Issue: In Honor of Professor Juan Bolaños. * L. Felipe Barros [email protected] 1
Centro de Estudios Científicos—CECs, 5110466 Valdivia, Chile
tumors [5]. Why would the brain shun oxygen and engage in inefficien
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